Excessive alcohol consumption is a major threat to human health. Normal host defense mechanisms are compromised in alcoholic patients, often resulting in pronounced frequency and severity of infections. Both clinical and experimental evidence suggest that alcohol alters the immune system. Chronic alcohol consumption impairs induction of human cell- mediated immune responses and elevates serum antibody levels. Studies from our laboratory during the initial granting period for this ongoing project, show that ethanol has a twofold effect on the immune response; it enhances specific humoral immunity and impairs induction of specific cell- mediated immunity. More specifically, ethanol enhances poly(Glu5OTyr50) (GT)-specific humoral immunity and impairs poly(Glu6OAla3OTyr10)(GAT)- specific cell-mediated immunity regulated by CD4-bearing helper (Th) lymphocytes designated Th2 and Th1, respectively. Despite the importance of alcohol in compromising host defense, little is known of the mechanism(s) underlying ethanol-caused immune alteration. New findings from our laboratory strongly suggest that ethanol alters cytokine expression, resulting in profound alteration of immune function. We propose that alteration of cytokine expression by ethanol plays a critical role in the modification of specific immune responses by alcohol consuming individuals. We propose to direct the activities of our laboratory toward three major goals: 1) To further define the conditions and the extent whereby ethanol alters the immune function in inbred strains of mice. 2) To determine which cells of the immune system are affected by ethanol consumption, and 3) To determine the underlying mechanism(s) for ethanol's alteration of specific immune function. Our laboratory is now in a position to critically assess how alcohol alters immune function. Our data suggest that one of the mechanisms whereby alcohol alters immune function is by the up- or downregulation of cytokine expression. These experiments are designed to critically evaluate whether alcohol or its metabolites affect cytokine expression in a manner that favors one type of immune function over another. These studies are critical to the development of therapeutic strategies for alcoholic patients who are a risk to infectious disease.